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Peripheral sympatholytic actions of four AT1 antagonists: are they relevant for long-term antihypertensive efficacy?

Dendorfer, Andreas; Dominiak, Peter; Tempel, Klaus; Raasch, Walter

doi: 10.1097/01.hjh.0000179510.86265.63
Original papers: Sympathetic mechanisms

Background Angiotensin II causes hypertension not only by direct constriction of vascular smooth muscle, but also by facilitating the release of noradrenaline from sympathetic terminals and by enhancing vascular noradrenaline sensitivity. AT1 receptor antagonists attenuate all these actions, but display some evidence of substance-related selectivities.

Objective The contribution of pre- or postsynaptic impairment of sympathetic transmission to long-term antihypertensive efficacy should be determined for four structurally different, clinically approved AT1 antagonists.

Design Spontaneously hypertensive rats were treated with candesartan, eprosartan, irbesartan, or losartan via osmotic minipumps for 4 weeks at doses yielding identical reductions of blood pressure. Maximum efficacy was obtained with a tripled dose of candesartan.

Methods In the pithed rat model, stimulus/response dependencies were determined for vasopressor effectivity of preganglionic electrical stimulation, and of intravenous bolus applications of noradrenaline and angiotensin II.

Results Losartan, irbesartan, eprosartan, and candesartan at doses of 5, 40, 20, and 0.05 mg/kg per day, were equally effective in reducing basal systolic blood pressure (−42 mmHg), and the vasopressor potency of angiotensin II (approximately 10-fold). The efficacies of preganglionic stimulation and exogenous noradrenaline were unaltered, with the exception of irbesartan, which reduced vascular noradrenaline sensitivity. The tripled dose of candesartan further reduced basal and angiotensin II-stimulated blood pressures, and significantly attenuated vascular noradrenaline sensitivity.

Conclusion AT1 antagonists at doses that effectively reduce blood pressure in chronic therapy do not generally suppress peripheral sympathetic function. A potential interaction consists in a reduction of vascular noradrenaline sensitivity, which can be considered as a class effect of AT1 antagonists at high dosage.

Institute of Experimental and Clinical Pharmacology and Toxicology, University Clinic Schleswig-Holstein, Campus Luebeck, Luebeck, Germany

Received 31 March, 2005

Revised 8 June, 2005

Accepted 10 June, 2005

Sponsorship: The following companies supported this study by supplying grants or test substances: AstraZeneca, Wedel, Germany; Bristol-Myers Squibb, München, Germany; MSD Sharp & Dohme, München, Germany; SmithKline Beecham Pharma, München, Germany.

Parts of this work have been published as an abstract: Dendorfer A, Raasch W, Tempel K, Dominiak P. Pre- and postsynaptic activities of four AT1 antagonists in SHR. JRAAS 2000; 1:91.

Correspondence and requests for reprints to Andreas Dendorfer, MD, Institute of Experimental and Clinical Pharmacology and Toxicology, University Clinic Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany. Tel: +49 451 5002684; fax: +49 451 5003327; email: dendorfe@medinf.mu-luebeck.de

© 2005 Lippincott Williams & Wilkins, Inc.